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Nephrol Dial Transplant (2001) 16: 1607-1614
© 2001 European Renal Association-European Dialysis and Transplant Association

Effect of chronic renal failure on the expression and function of rat intestinal P-glycoprotein in drug excretion

Céline Veau*,1, Christine Leroy*,1, Hélène Banide1, Daniel Auchère1, Sylviane Tardivel1,2, Robert Farinotti1 and Bernard Lacour1,2,

1 Laboratoire de Physiologie-Pharmacie Clinique, UPRES 2706, Faculté de Pharmacie, Châtenay-Malabry and 2 Laboratoire du Métabolisme Minéral des Mammifères, EPHE-Physiologie, Faculté de Pharmacie, Châtenay-Malabry, France

Background. In chronic renal failure, the renal excretion of certain drugs is dramatically reduced. To determine whether other routes of drug elimination, such as secretion through the intestinal barrier by intestinal P-glycoprotein can be altered, we compared P-glycoprotein activity, P-glycoprotein protein content, and P-glycoprotein mRNA levels in intestine of control and chronic renal failure rats.

Methods. Chronic renal failure was surgically induced in rats by partial (7/8) nephrectomy. After 5 weeks, intestinal transport of rhodamine 123, a P-glycoprotein substrate, was carried out using an in vitro model of everted gut sacs. P-glycoprotein protein content was quantified by enzyme-linked immunosorbent assay and P-glycoprotein mRNA expression was evaluated by semi-quantitative reverse transcriptase polymerase chain reaction.

Results. A decrease of intestinal rhodamine 123 transport was observed in chronic renal failure rats, pointing to an inhibition of P-glycoprotein activity. Transport was inhibited in both sham-operated rats and rats with chronic renal failure by verapamil and cyclosporin A, but relative inhibition vs baseline was less marked in chronic renal failure than in sham-operated rats. In contrast, no significant differences in levels of P-glycoprotein protein or mRNA were observed between the two groups.

Conclusions. Intestinal secretion of rhodamine 123 is mainly mediated by P-glycoprotein. It was reduced in rats with chronic renal failure, reflecting reduced intestinal drug elimination via a decrease in P-glycoprotein transport activity rather than via protein underexpression.

Keywords: chronic renal failure; intestine; P-glycoprotein; rat; rhodamine 123; semi-quantitative RT-PCR

*These two authors contributed equally to this work.

Correspondence and offprint requests to: Bernard Lacour, Laboratoire de Physiologie-Pharmacie Clinique, Faculté de Pharmacie, F-92296 Châtenay-Malabry Cedex, France.


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